Leukemic cutaneous T cell lymphoma (L-CTCL) is a non-Hodgkins lymphoma derived from skin tropic L-selectin/CCR7+ central memory T cells (TCM). The prognosis for advanced L-CTCL is poor and most systemic therapies are partially effective in only 30% of patients. We report that alemtuzumab (CD52), an antibody that depletes circulating T and B cells, induces complete remission in 50% of patients with refractory L-CTCL and is not associated with increased infection, despite the absence of circulating T and B cells in these patients. We find that CD52 depletes all T cells in blood and selectively purges the skin of L-selectin/CCR7+ central memory T cells (TCM), including the malignant clone, while leaving a large diverse population of skin resident effector memory T cells (TEM) intact. In mice, tissue resident TEM are sessile, non-recirculating T cells that can function alone to protect barrier tissues from infection but these cells have never been studied in humans. We hypothesize that alemtuzumab depletes only circulating T cells because T cell killing occurs via ADCC involving cell types abundant in the circulation but largely absent in skin. Second, we hypothesize that malignant L-CTCL T cells are depleted from skin because they are TCM that recirculate between the skin and blood, whereas skin resident TEM are spared because they are sessile and non-recirculating. Using humanized mice, we will study the mechanism by which CD52 depletes malignant T cells from blood and skin but spares skin resident TEM. We will characterize the effects of CD52 therapy on the human immune system, identifying elements spared by CD52 therapy that underlie the resistance of these patients to infection. Aside from controlling the malignant T cell population, two major challenges in treating L-CTCL patients are their tendencies to suffer from intractable, debilitating pruritus and to develop cutaneous infections. We find that both malignant and benign T cells in L-CTCL are markedly Th2-biased. We hypothesize that aberrant overproduction of Th2 cytokines leads to pruritus, reduced Th1 function and reduced antimicrobial peptide (AMP) production in skin, contributing to infectious susceptibility. Paradoxically, CD52 therapy strongly diminishes Th2 cytokine production and enhances Th1 cytokine production. We will determine if this is associated with enhanced in vitro T cell reactivity to known pathogens, improved reactivity in dermal antigen skin tests, restoration of AMP production and lower levels of Staph colonization of the skin. In short, we predict that depletion of both benign and malignant TCM in the setting of L-CTCL actually enhances the function and protective ability of remaining skin resident TEM and that cutaneous immunity is stronger as a result. Successful completion of our studies will support the use of CD52 as a first line therapy for L-CTCL that depletes malignant T cells while sparing and enhancing normal immunity. Our work will also provide critical insights into human immunobiology, providing the first evidence in humans that TCM are migratory, TEM are nonmigratory, and that TEM can provide immune protection of the skin in the absence of TCM.